Colorectal cancer (CRC) is a multifactorial complex disease with both genetic and environmental factors contributing to the etiology of this severe disease. First results from genome-wide association studies (GWAS) have demonstrated considerable success in identifying new loci in common complex diseases, including CRC and additional loci are expected to be identified through combined analyses of individual GWAS. as proposed in Area 1 of our proposal. However, to fully explore the impact of common genetic variants on the risk of CRC it will be important to explore interactions between genetic variants as well as between genetic variants and environmental risk factors. CRC is associated with several modifiable environmental factors, such as obesity, physical activity, aspirin use, smoking and diet providing the opportunity to test gene-environment (GxE) interactions and potentially provide targeted intervention. To expedite the translation of these findings into the clinic and public health it is critical to understand the penetrance of the newly identified loci and develop and validate risk models, including both environmental and genetic risk factors. To comprehensively explore these questions we propose the following specific aims;(1) To investigate whether associations with genetic variants are modified by environmental risk factors for CRC, including age, sex, family history of CRC, obesity, physical activity, non-steroidal antiinflammatory drugs, postmenopausal hormone use, folate, calcium, red meat, alcohol, and smoking. This will entail both scanning across the genome for GxE interactions in four GWAS and a large replication in independent study populations. (2) To determine the penetrance and population attributable risk of all identified CRC susceptibility loci within both high risk family and population-based studies. (3) To develop complex risk models that incorporate genetic variants identified in Area 1 and 2 along with environmental risk factors in population-based and prospective studies. As part of this aim we will evaluate the clinical and public health validity of these risk models. This Consortium provides an unprecedented opportunity to accelerate the translation of GWAS findings for CRC into the clinic and public health. The expertise of our transdisciplinary team, the large sample size, and the detailed exposure ascertainment in population-based and prospective studies provide a unique resource for integrative post-GWAS discovery research. We are facing a time of premature use of GWAS findings for genetic testing that will likely lead to confusion in our community. Comprehensive evaluation and characterization of GWAS findings with respect to interactions with environmental risk factors, penetrance, and risk models is needed to provide a rigorous knowledge base for targeted public health and clinical interventions.